|Title of Invention||
A PROCESS FOR THE PREPARATION OF FOSINOPRIL SODIUM FORM A
|Abstract||The present invention relates to a process for the preparation of Fosinopril sodium Form A from fosinopril by treating it with sodium metal carrier in the presence of ethyl acetate containing 0.5% to 5% of water.|
FIELD OF THE INVENTION
The present invention relates to a process for the preparation of Fosinopril sodium Form A.
BACKGROUND OF THE INVENTION
Fosinopril, also known as ([l.[S*(R*)],2a.,4P]-4-cyclohexyl-l-[[[2-methyl-l-(l-oxopropoxy)propoxy](4-phenylbutyl)phosphinyl]acetyl]-L-proline, is a useful antihypertensive agent and is marketed as the sodium salt, having the chemical structure of Formula I.
Fosinopril and its salts have been first disclosed generically in US patent 4,337,201. Fosinopril is known to exhibit polymorphism as disclosed in US 5,162,543. Two polymorphs of Fosinopril sodium, Form A and Form B have been reported along with their method of preparation. Polymorphic form A of Fosinopril sodium has been prepared in the above patent by treating Fosinopril or its salt in alcohol or ketonic solvent having water in the ratio of 0.2% or more with respect to solvent. Form B is prepared by using water less than 0.2%.
Another PCT application WO 02/088149 describes the process for the preparation of Fosinopril sodium Form A. Form A may be prepared by crystallizing Fosinopril sodium in a solvent or mixture of solvents such as N,N-
dimethylacetamide, MA^-dimethylformamide, tetrahydrofuran, methylene chloride, ethyl acetate, toluene or the like and water content used preferably is less than 0.2%.
PCT application WO 03/045961 Al describes a process to prepare polymorphic forms of Fosinopril using oxygen containing solvents and nitriles or mixtures thereof provided that solvent and mixture of solvents should contain more than 0,4% v/v of CrC4 alcohol, and less than 0.2% (v/v) of water.
Alternatively, polymorphic Form A is prepared using tetrahydrofuran, with no other solvent mixture, containing less than 0.2% (v/v) of water.
In view of the above, the ratio of water content is very important to prepare different polymorphic forms of fosinopril sodium. In most of the references water content is less than 0.2% to prepare Form A, and if it is more, then solvent is either ketone or alcohol.
The present invention relates to yet another approach to prepare Form A of Fosinopril sodium where water content is more than 0.2% of the solvent used.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1: X-ray Diffaraction pattern of Form A of Fosinopril sodium.
Fig. 2: Infrared diffuse reflectance spectrum of Form A of Fosinopril sodium.
SUMMARY OF THE INVENTION
Accordingly, the present invention relates to a process for the preparation of Fosinopril sodium Form A, which comprises:
- treating a solution of Fosinopril in an ester solvent containing water in the range of 0.5% to 5.0% with sodium metal carrier in same solvent,
- stirring the reaction mass for sufficient time at a temperature of 0-60°C to crystallize Form A and
- isolating Form A of Fosinopril sodium. DETAILED DESCRIPTION OF THE INVENTION
Fosinopril may be prepared by the method reported in the prior art.
Polymorphic Form A is prepared by treating Fosinopril in solvent such as esters for example ethyl acetate, methyl acetate, isopropyl acetate and the like, containing 0.5 to 5% of water with sodium metal carrier. Specifically ethyl acetate is used and contains water preferably in the range of 1-1.5%. The sodium metal carrier is selected from sodium acetate, sodium carbonate, sodium bicarbonate and sodium 2-ethylhexanoate and preferably sodium 2- ethylhexanoate is used. The reaction is carried out at a temperature of 0-60°C and typically the crystallization is carried out at lO-SO^^C. It takes about 5-15 hours for complete crystallization. The infrared diffuse reflectance spectrum and X-ray diffraction pattern of the product obtained are matching with that reported for Form A in prior art.
The major advantage realized in the present invention is that no organic solvent mixture is used and water content is not restricted to less than 0.2%. The recovered solvent can also be recycled, lowering the cost of production.
The following specific examples illustrate the process of the invention.
PREPARATION OF FOSINOPRIL SODIUM FORM A
A solution of sodium 2- ethylhexanoate (1.35 g) in ethyl acetate (15 ml having moisture content 1.16 % w/w) was added to the solution of fosinopril (4.15 g) in ethyl acetate (45 ml having moisture content 1.16 % w/w) at 20-30°C. The reaction mixture was stirred for 10 hours at 10-30°C and the solid which crystallized out was filtered, washed with ethyl acetate (10 ml; having moisture content 1.16 % w/w) and dried under reduced pressure at 35-40°C to yield Fosinopril Sodium Form - A.
1. A process for the preparation of Fosinopril Sodium Form A, which comprises,
- treating solution of Fosinopril in an ester solvent containing water in the
range of 0.5% to 5.0% with sodium metal carrier.
" stirring the reaction mass for sufficient time at a temperature of 0-60'^C to crystallize Form A and
- isolating Fosinopril sodium Form A.
2. The process according to claim 1, wherein the ester solvent used is ethyl acetate.
3. The process according to claim 2, wherein ethyl acetate contain 1-1.5% v/v of water.
4. The process according to claim 1, wherein sodium metal carrier is selected from sodium acetate, sodium carbonate, sodium bicarbonate and sodium 2- ethylhexanoate.
5. The process according to claim 4, wherein sodium metal carrier is sodium 2- ethylhexanoate.
6. The process according to claim 4, wherein the crystallization is preferably carried out at 20-30°C.
7. The process according to claim 1, wherein sodium metal carrier is added in a solution form by dissolving it in ester solvent.
1322-CHE-2004 AMANDED CLAIMS 07-01-2010.pdf
1322-CHE-2004 AMANDED PAGE OF SPECIFICATION 07-01-2010.pdf
1322-che-2004 correspondence others.pdf
1322-che-2004 correspondence po.pdf
1322-CHE-2004 EXAMINATION REPORT REPLY RECIEVED 07-01-2010.pdf
|Indian Patent Application Number||1322/CHE/2004|
|PG Journal Number||7/2010|
|Date of Filing||06-Dec-2004|
|Name of Patentee||AUROBINDO PHARMA LIMITED|
|Applicant Address||PLOT NO.2, MAITRIVIHAR COMPLEX(Regd. office) AMEERPET, HYDERABAD-500 038.|
|PCT International Classification Number||A61K 31/675|
|PCT International Application Number||N/A|
|PCT International Filing date|